Estrogen signaling is mediated through two estrogen receptor isoforms, ERalpha and ERbeta. Dissecting the biological actions of these two receptors will have profound implications in developing new approaches for the treatment and prevention of diseases such as breast cancer and osteoporosis. The biological activities of estrogen can be attributed to distinct ligand-receptor interactions that alter protein structure and enable ER to interact with different cofactors. The overall objective of the proposed research is to develop novel pharmacotherapies for use in the treatment of breast cancer. To achieve this goal, combinatorial phage display technology will be used to identify novel peptides that interact specifically with ERbeta and modulate the transcriptional activity of the receptor. Characterization of the peptide interaction with ER will provide insight into the relationship between receptor conformation and function. Experiments that introduce the peptides into cells will address the efficacy of the peptide to inhibit ER action. Introduction of peptide antagonists into whole animals will aid in dissecting the pathways of estrogen signaling and will identify specific biological responses elicited by ERBETA.